Since its discovery, the Ubiquitin Proteasome System (UPS) has been recognized for its major role in controlling most of the cell's metabolic pathways. In addition to its essential role in the degradation of proteins, it is also involved in the addressing, signaling or repair of DNA, which makes it a key player in cellular homeostasis. Although other control systems exist in the cell, the UPS is often referred to as the conductor. In view of its importance, any deregulation of the UPS leads to more or less severe disorders for the cell and therefore the body, the UPS being involved in many pathologies (cancer, Alzheimer's disease, Huntington's disease, etc.). UPS is made up of more than 1000 different proteins, the combinations of which allow the fine targeting of virtually all proteins in the body. UPS uses an enzymatic cascade (E1 [2 members], E2 [40], E3 [> 700]) which allows the transfer of ubiquitin, a small protein of 8.5 kDa on the protein to be targeted either for its degradation or to modify its activity. This ubiquitination signal is reversible and many deubiquitinases (DUB,  80) also have an important role. E3 enzymes are the most numerous and their function is to recognize the target protein, which makes them important players in the specific action of UPS and therefore attractive therapeutic targets to fight against various pathologies such as cancer. The very nature of E3s and the complexity of the interactions they perform with different partners offer a very broad field of investigation and therefore significant potential for the development of therapeutic approaches. Without being exhaustive, this review illustrates the different strategies that have already been implemented to fight against different pathologies (excluding bacterial or viral infections).